1. Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA
2. Departments of Reproductive and Vascular Biology Institute of Biomedical Research, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
3. Birmingham Women's Hospital, Edgbaston, Birmingham B15 2TG, UK
4. Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6142, USA
5. Joint Research Division Vascular Biology, Medical Faculty Mannheim, University of Heidelberg, and German Cancer Research Center Heidelberg, 69120 Heidelberg, Germany
6. Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
7. Program in Vascular Biology, Department of Surgical Research, The Children's Hospital Boston, Boston, Massachusetts 02215, USA
8. School of Medicine, Virginia Commonwealth University, Richmond, Virginia 23298, USA
9. Harvard–Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston, Massachusetts 02215, USA
10. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA
11. Deceased.

Correspondence to: Raghu Kalluri^1,9,10 Correspondence and requests for materials should be addressed to R.K. (Email: rkalluri@bidmc.harvard.edu).

Abstract

Despite intense investigation, mechanisms that facilitate the emergence of the pre-eclampsia phenotype in women are still unknown. Placental hypoxia, hypertension, proteinuria and oedema are the principal clinical features of this disease. It is speculated that hypoxia-driven disruption of the angiogenic balance involving vascular endothelial growth factor (VEGF)/placenta-derived growth factor (PLGF) and soluble Fms-like tyrosine kinase-1 (sFLT-1, the soluble form of VEGF receptor 1) might contribute to some of the maternal symptoms of pre-eclampsia^{1, 2, 3, 4, 5}. However, pre-eclampsia does not develop in all women with high sFLT-1 or low PLGF levels, and it also occurs in some women with low sFLT-1 and high PLGF levels^{5, 6}. Moreover, recent experiments strongly suggest that several soluble factors affecting the vasculature are probably elevated because of placental hypoxia in the pre-eclamptic women, indicating that upstream molecular defect(s) may contribute to pre-eclampsia. Here we show that pregnant mice deficient in catechol-O-methyltransferase (COMT) show a pre-eclampsia-like phenotype resulting from an absence of 2-methoxyoestradiol (2-ME), a natural metabolite of oestradiol that is elevated during the third trimester of normal human pregnancy. 2-ME ameliorates all pre-eclampsia-like features without toxicity in the Comt^-/- pregnant mice and suppresses placental hypoxia, hypoxia-inducible factor-1 expression and sFLT-1 elevation. The levels of COMT and 2-ME are significantly lower in women with severe pre-eclampsia. Our studies identify a genetic mouse model for pre-eclampsia and suggest that 2-ME may have utility as a plasma and urine diagnostic marker for this disease, and may also serve as a therapeutic supplement to prevent or treat this disorder.

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